PROJECT SUMMARY Spinal manipulative therapy (SMT) is a non-pharmacologic, complementary and integrative health mind and body intervention that is widely used to treat chronic pain. However, the mechanism of analgesic action of SMT is not understood. Information is particularly sparse with respect to neuropathic pain, which exerts devastating personal and socioeconomic burdens. Pharmacological agents are the mainstay of symptoms management for neuropathic pain, but relief is weak and temporary, often associated with major adverse outcomes. For example, there is an epidemic of opiate addiction, abuse, and overdose. To begin to fill this knowledge gap, we have developed an innovative rat model of a frequently used non-thrust SMT technique, low velocity variable amplitude spinal manipulation (LVVA-SM). Our preliminary data in a well-characterized rat model of chronic peripheral neuropathic pain (spared nerve injury) indicate that LVVA-SM (10 min, 0.16Hz, 20 flexion, at the L5 vertebra) administered with our custom-made motorized device decreases behavioral signs of chronic pain (hindpaw mechanical allodynia). Our long-term goal is to determine the neurobiological mechanisms underlying this anti-allodynic effect of LVVA-SM. This R15 application proposes to leverage a multidisciplinary collaboration to characterize LVVA-SM-induced anti-allodynia (Aim 1) and then to determine whether this is mediated by endogenous activation of cannabinoid receptors in the spinal cord dorsal horn (Aim 2), an important site of nociceptive transmission. The project is directly relevant to the chiropractic profession's interest in taking an evidence-based approach to treating chronic pain and strengthening Palmer College of Chiropractic's research environment. The goals of the R15 program are strongly aligned with Palmer's research mission, namely to conduct meritorious research on SMT and provide an opportunity for students to learn about biomedical research through mentored hands-on participation. If successful, this project will provide clinicians with potentially translatable data that will improve the rationale for and the efficacy of SMT.